tbuckley/cabot-search huggingface dataset:
CTNI-39. REGOMA-OS: A LARGE ITALIAN MULTICENTER, PROSPECTIVE, OBSERVATIONAL STUDY ANALYZING REGORAFENIB EFFICACY AND SAFETY IN RECURRENT GLIOBLASTOMA PATIENTS
Authors: Mario Caccese, Isacco Desideri, Veronica Villani, Matteo Simonelli, Michela Buglione, Silvia Chiesa, Enrico Franceschi, Paola Gaviani, Irene Stasi, Claudia Caserta, Sonia Brugnara, Ivan Lolli, Elisa Bennicelli, Paola Bini, Angelo Salvatore Cuccu, Silvia Scoccianti, Giovanna Magni, Gian Luca De Salvo, Vittorina Zagonel, Giuseppe Lombardi
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND in the randomized phase 2 REGOMA trial, regorafenib (REG) showed promising activity in recurrent glioblastoma (GBM) patients (PTS); subsequently, in Italy the National Health System has permitted the reimbursement of the REG as second-line therapy. We performed a large multicenter, prospective and observational study to confirm REGOMA data in a real-world setting. Materials and METHODS major inclusion criteria were: histologically confirmed diagnosis of GBM according to WHO 2016 and relapse after Stupp treatment, good performance status (ECOG PS 0-1), good liver function. REG was administered at standard dose of 160mg/die for 3 weeks on/1 week off. Brain MRI was performed within 14 days before starting REG and every 8-12 weeks, subsequently. Primary endpoint was overall survival. RANO criteria were used for response evaluation, CTACAE v. 5 for adverse events. RESULTS from Sept 2020 to Oct 2022, 192 recurrent GBM PTS were enrolled from 29 Cancer Centres in Italy: median age was 58ys (IQR 52.8-67.0), 68% male, ECOG PS was 0 in 85 (44%), 115 PTS (60%) undertook steroids at baseline. MGMT was methylated in 43%, IDHwt in 92%. Median follow-up was 16.6 months (IQR 12.6-19.6). Median OS was 8.2ms (95% CI 6.5-9.6), 12ms-OS 34.7% (95%CI 27.2-42.4); median PFS was 2.6ms (95%CI 2.3-2.9), 6ms-PFS 14.3%. Radiological response was PR and SD in 12 (8%) and 25 (16%) PTS. 77 (44%) PTS received third-line therapy. The median of REG cycles per patient was 3 (IQR 2.0-4.0). Grade 3-4 adverse events (AE) were reported in 53 (28%) PTS; reduction/delay and permanent discontinuation due to AE in 36% and 8% of PTS. No death was considered as treatment-related AE. CONCLUSIONS compared to the REGOMA trial, this large Italian multicenter, prospective and observational trial confirmed the results in terms of overall survival with a good toxicity profile of REG in recurrent GBM PTS.
SURG-07. CLIVAL CHORDOMA: A COMPREHENSIVE META-ANALYSIS OF OPERATIVE MARGINS, PROGRESSION FREE SURVIVAL, AND OVERALL SURVIVAL
Authors: Nolan Brown, Cathleen Kuo, Oanh Nguyen, Zachery Neil, Julian Gendreau
Journal: Neuro-Oncology (2023)

Abstract Despite their precarious behavioral classification (histopathologically benign (low-grade), behaviorally malignant), great strides have been taken to improve prognostication and treatment paradigms for patients with skull base chordoma. However, due to the rarity of this tumor, prior investigations remain limited to small retrospective series. Accordingly, we performed a systematic review and meta-analysis in order to profile surgical and survival outcomes for skull base chordoma. Fixed and random-effect meta-analyses were performed for categorial variables including number of males, GTR, STR, 5-year OS, 10-year OS, 5-year PFS, and 10-year PFS. Following the systematic search and screen, 47 studies published between 1993-2020 reporting data for 2204 patients remained eligible for analysis. Sex distribution was comparable between males and females, with a slight predominance of male-identifying patients (0.5625 [0.5418;0.3909]). Average age at diagnosis was 42.4 ± 12.5 years, while average age of treatment initiation was 43.0 ± 10.6 years. Overall, there was a substantial degree of heterogeneity across the 47 studies (I^2=56.3% [44.0%; 65.9%]). With respect to operative margins, the rate of GTR was 0.3323 [0.2824; 0.3909], I^2 = 91.9% [90.2%; 93.4%], while the rate of STR was significantly higher at 0.5167 [0.4596; 0.5808], I^2 = 93.1% [91.6%; 94.4%]. Interestingly, 5-year OS rate was 0.7113 [0.6685; 0.7568], I^2 = 91.9% [90.0%; 93.5%]. Furthermore, 10-year OS rate was 0.4957 [0.4230; 0.5809], I^2 = 92.3% [89.2%; 94.4%], which was comparable to both 5-year PFS rate of 0.5054 [0.4394; 0.5813], I^2 = 84.2% [77.6%; 88.8%] and 10-yr PFS rate of 0.4949 [0.4075; 0.6010], I^2 = 14.9% [0.0%; 87.0%]. There were 55 reported deaths for a perioperative mortality rate of 2.5%. The most common complication was CSF leak(5.4%). Overall, these results indicate good 5-year outcomes; however, 10-year prognosis for skull base chordoma remains poor due to its radiotherapeutic resistance and high recurrence rate.
CTIM-22. PHASE I STUDY RESULTS OF THE ANTIBODY-CYTOKINE FUSION PROTEIN L19TNF IN COMBINATION WITH LOMUSTINE FOR PATIENTS WITH RECURRENT GLIOBLASTOMA REVEAL PROMISING SAFETY AND DURABLE TUMOR RESPONSES
Authors: Tobias Weiss, Emanuele Puca, Alfredo Covelli, Dorothee Gramatzki, Patrick Roth, Dario Neri, Teresa Hemmerle, Michael Weller
Journal: Neuro-Oncology (2023)

Abstract Treatment options for recurrent glioblastoma are limited and there is a need for novel effective therapies. Recently, we showed synergistic preclinical anti-tumor activity of the immunocytokine L19TNF in combination with lomustine in orthotopic immunocompetent glioma mouse models. L19TNF is an antibody-cytokine fusion protein, comprising the pro-inflammatory cytokine tumor necrosis factor (TNF) fused to the antibody L19 that binds to a tumor-specific epitope of the extracellular matrix protein fibronectin. This allows a targeted delivery of therapeutically relevant doses of TNF to the tumor site through intravenous administration while sparing healthy tissues. Here, we present results of the completed phase I part of a phase I/II open label, multicenter, randomized study to investigate L19TNF in combination with lomustine for patients with recurrent glioblastoma (NCT04573192). Fifteen patients were enrolled from February 2021 – January 2023 and treated at three different dose levels of L19TNF in combination with lomustine. Overall, the treatment was well tolerated. The most common adverse events were asymptomatic increase of liver function tests and a decrease of white blood cells and platelets. Serial MRI assessments revealed near-complete responses in 3 patients (20%) and stable disease in 8 (53%) patients. The median progression-free survival was 4.2 months, progression-free survival rate at 6 months was 46% (7/15 patients), and median overall survival has not been reached after a median follow-up of 11 months. Serial blood assessments demonstrated a treatment-associated increase in C-reactive protein, a peripheral marker for inflammation, which correlated with progression-free survival. A patient, who showed a near-complete response that lasted 12 months relapsed at a different location. Subsequent re-challenge with L19TNF and lomustine again led to a partial response. These encouraging results justify further investigations within the phase II part of the clinical trial that is recruiting patients in four countries.
BIOM-15. CIRCULATING EXOSOMES CORRELATE WITH RADIOGRAPHIC PROGRESSION IN GLIOBLASTOMA PATIENTS AFTER ULTRASOUND-BASED OPENING OF THE BLOOD-BRAIN BARRIER
Authors: Mark W Youngblood, Abha Kumari, Andrew Gould, Yoon-Tae Kang, Li Chen, Karl Habashy, Christina Amidei, Rachel Ward, Cristal Gomez, Guillaume Bouchoux, Michael Canney, Roger Stupp, Sunitha Nagrath, Adam Sonabend
Journal: Neuro-Oncology (2023)

Abstract Non-invasive methods to detect progression of glioblastoma (GBM) are needed to optimize patient management. Circulating blood-based biomarkers for GBM progression are limited by the blood-brain barrier, which restricts leakage of tumor-related elements into circulation. To address this, we investigated circulating GBM-associated exosomes using samples obtained as part of a clinical trial where the blood-brain barrier was temporarily opened with a skull-implantable ultrasound system (NCT04528680). Samples were collected after an intra-operative sonication procedure at multiple time points, as well as longitudinally before and after subsequent outpatient sonication cycles. Plasma exosomes were isolated using a newExoChip microfluidic device, and enrichment of tumor-derived exosomes was based on expression of Phosphatidylserine (which binds to Annexin V on the device). Tumoral origin of the exosomes was validated with GBM cell lines as positive controls, using Western blots and variant-specific ddPCR to confirm tumor contents. We observed a 2.1-fold increase in exosome concentration in plasma samples obtained intraoperatively between 2 and 45 minutes after sonication, relative to pre-operative baseline (n = 4 patients; 19 plasma samples; one-tailed t-test p = 0.02). In a longitudinal analysis of eight patients, volumetric MRI analysis of enhancement was compared with changes in exosome concentration after sonication. Among patients with short progression-free survival (PFS) (n = 4; PFS &amp;lt; 90 days), multi-subject analysis yielded a repeated-measures correlation of -0.59 (p = 0.06), compared to 0.01 among long PFS patients (p = 0.96). In both cohorts, use of raw pre-sonication exosome concentrations had less association with MRI enhancement (p = 0.67 and 0.98 respectively). Considering each sample independently, we found the average Pearson correlation among short PFS patients was 0.73 (avg. p = 0.39), while no correlation was seen among long PFS patients (avg. r value = 0.10; avg. p-value = 0.54). Circulating exosomes hold promise as a non-invasive method to track GBM progression upon opening of the blood-brain barrier. Further refinement and validation in larger cohorts is warranted.
SURG-09. TARGETING A SHARED GLIOBLASTOMA CELL STATE THROUGH ADAPTIVE NATURAL KILLER CELLS AUGMENTED WITH TRISPECIFIC KILLER CELL ENGAGER (TRIKE) IMMUNE-MODULATOR AGAINST CD276
Authors: Jianfang Ning, Zachary Davis, Shan Zhu, Jeffrey Miller, Clark Chen
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION T and NK (Natural Killer) cells have emerged as promising platforms for immunotherapy. While T cells require antigen priming and complex MHC-dependent interactions, NK cells exhibit limited persistence and limited antigen specificity. Trispecific Killer cell Engagers (TriKEs) are constructs developed to address these limitations, combining interleukin 15 (IL15, to enhance persistence), a single-chain antibody fragment against CD16 (to immune-activate NK), and a second fragment targeting a tumor surface marker. Objective: In this study, we identified CD276 (B7H3) as the surface marker optimal for an anti-glioblastoma TriKE and tested its effect on the anti-glioblastoma activity of NK cells. Method: Mass-spectrometry, RNA-Seq, and single cell RNA-Seq profiling of glioblastoma lines. Laboratory characterization and murine modeling Result: Orthogonal analysis of mass-spec identified cell surface molecules enriched in glioblastoma lines and RNA-seq of lines with defined sensitivity to NK cells identified surface proteins highly expressed in NK-resistant lines. Screening of these candidates for genes that showed poor survival association using the TCGA identified CD276. qPCR analysis confirmed higher CD276 expression in the NK-resistant lines, though expression is also detected in NK-sensitive glioblastoma lines. Western blotting analysis and TCGA analysis showed higher level CD276 expression in all glioblastoma subtypes (proneural, neural, mesenchymal, and classical) relative to normal brain. Single cell RNA-Seq of clinical specimens confirmed high expression of CD276 in glioblastoma cells in OPC-like, NPC-like, AC-like, and MES-like cell states. Co-incubation of a IL15, CD16, and CD276 targeting TriKE with either adaptive or iPS derived NK cells enhanced anti-glioblastoma cytotoxicity against cells otherwise refractory to NK treatment in vitro. Synergy between these reagents were also observed in vivo upon orthotopic injection. CONCLUSION Our results suggest that a therapeutic strategy combining intra-tumoral injections of NK cells and a B7H3 specific TriKE holds promise and warrants clinical trial consideration.
NCOG-13. OUTCOMES OF CNS WHO GRADE 2 OLIGODENDROGLIOMA IN ADULT PATIENTS ; IMPACT OF ADJUVANT TREATMENT ON OVERALL RESULTS
Authors: Yukyeng Byeon, Sang Woo Song, Chaejin Lee
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE Patients with oligodendroglioma (ODG), isocitrate dehydrogenase (IDH)-mutant, 1p19q codeleted, CNS WHO grade 2 have a median overall survival of longer than 10 years. Patients with ODG who are high-risk by RTOG criteria are offered radiation in combination with procarbazine, lomustine, and vincristine (PCV). The study aims to analyze the patient’s outcomes and assess the efficacy of postoperative treatment. METHODS A total of 138 adult patients who underwent resection for newly diagnosed grade 2 ODG between 1994 and 2021 were enrolled. Sixty-three (45.7%) were observed after gross total resection (GTR) or near total resection (NTR), 5 (0.4%) received adjuvant treatment after GTR or NTR, 37 (26.8%) were observed after subtotal resection (STR) or biopsy, and 33 (24.0%) received adjuvant treatment after STR or biopsy. The study analyzed progression-free survival (PFS), overall survival (OS), and risk variables. RESULTS Out of the 138 patients, 38 (27%) patients received adjuvant treatment, with 30 of them (78.9%) underwent radiotherapy only, 6 (15.8%) underwent radiochemotherapy, and 2 (5.3%) received chemotherapy alone. The median PFS was 6.8 years. Multivariate analysis revealed STR or biopsy (p=0.04), initial MR imaging enhancement (p=0.002), and postoperative observation(p=0.006) were associated with poorer PFS outcomes. The 5-year overall survival rate was 95.5% and the 10-year overall survival was 76.1%. Poor OS prognosis was associated with STR or biopsy (p=0.03), preoperative seizure (p=0.002), and initial MR imaging enhancement (p&amp;lt; 0.001). CONCLUSIONS : GTR and NTR is essential for achieving prolonged PFS and OS in ODG patients. Postoperative treatment is associated with favorable PFS outcomes but does not significantly affect OS. For an accurate diagnosis and appropriate treatment, the utmost care should be taken to avoid underestimating the results of the biopsy.
SURG-23. THE INFLUENCE OF PRE-OPERATIVE VARIABLES ON SURVIVAL OF PATIENTS WITH GLIOBLASTOMA
Authors: Sabrina Begley, Isabelle Pelcher, Michael Schulder
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is both the most common and most aggressive brain tumor in adults. Despite treatment advances, prognosis remains poor and is influenced by numerous factors. METHODS Patients treated at our institution for glioblastoma were reviewed to identify pre-treatment factors that could increase survival time. 183 treated for high-grade GBM between 2017 and 2021 with complete follow-up data were included. Overall (OS) and progression-free survival (PFS) were calculated with Kaplan-Meier analysis. Cox regression analysis identified the influence of several pre-treatment factors (age, Karnofsky performance status (KPS), radiographic distribution of tumor, and MGMT methylation status) on survival time. RESULTS Average age was 64.9 years. At presentation, 69.9% of patients had KPS &amp;gt; 80. Multifocal tumors occurred in 24.6% of patients, involving an average of 2 distinct regions (either multifocal or unifocal lesions). MGMT methylation was confirmed in 17.5% of patients. Recurrence occurred in 46.4% of patients. Median OS was 21.6 (14.3 – 28.9) months and PFS was 13.4 (10.6 – 16.1) months. MGMT methylation was associated with significantly longer median OS (36.9 vs. 17.0 months, p = 0.012) and PFS (20.0 vs. 10.3 months, p = 0.002) compared to those without. Cox regression confirmed MGMT methylation to be significantly associated with longer PFS (HR -0.883, p = 0.004) and OS (HR -0.785, p = 0.014). Age (HR 0.03, p = 0.003) and KPS &amp;gt; 80 (HR -0.7, p = 0.006) significantly impacted OS, but not PFS. Tumor extent did not impact survival. CONCLUSIONS We found that multifocal tumor, greater number of involved regions. and older age were associated with shorter OS, while MGMT methylation was associated with longer OS. Similar correlations were found for PFS. In upcoming trials, these factors may need to be controlled for between groups in order to accurately determine the effect of new treatments.
BIOM-42. LONGITUDINAL IMMUNE PROFILES OF LOWER GRADE ADULT GLIOMA PATIENTS
Authors: Geno Guerra, Stephen Francis, Annette Molinaro, Jennie Taylor, Gayathri Warrier, Paige Bracci, Terri Rice, Helen Hansen, Lucie McCoy, Jennifer Clarke, John Wiencke, Margaret Wrensch
Journal: Neuro-Oncology (2023)

Abstract Immune dysregulation is a known characteristic of glioma, however there is little known about the peripheral immune status of lower-grade (LrGG) glioma patients across the course of disease. Using immunomethylomic (deconvoluted blood DNA methylation) data from the UCSF Immune Profiles Study, we explore changes in patient peripheral blood immune cell profiles in newly diagnosed and recurrent LrGG patients. For patients receiving radiation (RT) and temozolomide (TMZ) (n = 75), blood is collected pre-RT/TMZ, post-RT/TMZ, before, during, and after adjuvant TMZ (if applicable). For patients followed only by MRI (n = 53) and those with other treatment plans (n = 67), blood is collected at MRIs, and if applicable, before radiation. For all patients, blood is also collected before new treatment intervention. For patients (LrGG IDH mutated) with paired pre- and post-surgery samples (n = 139), we observed a significant post-surgery increase in the count of memory B-cells (p = 1.7e-5), neutrophils (p = 0.0001), basophils (p = 8.7e-5), monocytes (p = 0.0001), and T-regulatory cells (p = 0.0001) along with a significant decrease in natural killer cells (p = 0.0003). Treatment was also associated with altered patient immune profiles. The use of dexamethasone was associated with an increased count of B-memory (p = 0.0001) and B-naïve cells (p = 0.0001), monocytes (p = 2.1e-5), and neutrophils (p = 3.7e-6) post-surgery. Patients receiving chemoradiation (n = 12) exhibited significant and temporally sustained decreases in B-memory (p &amp;lt; 0.0001), B-naïve (p = 0.005), CD4 naïve cells (p = 0.002), and in neutrophils (p = 0.001). Patient follow-up, data collection, and further analyses are ongoing. These results shed light on the dynamic and variable immune changes in LrGG patients and provide a guide for future prognostic and therapeutic studies.
DDDR-03. DRUG REPURPOSING VIA ULTRA-HIGH THROUGHPUT 3D SPHEROIDS SCREENING FOR HUMAN SCHWANNOMA
Authors: Kecheng Lei, Muhibullah Tora, Yuliya Lakhina, Michelle Zhang, Min Qui, Haian Fu, Yuhong Du, Nicholas Boulis
Journal: Neuro-Oncology (2023)

Abstract Schwannoma is the most common benign peripheral nerve tumor occurring sporadically or as part of neurofibromatosis syndromes. While surgical resection can be used as the primary treatment option for Schwannoma, patients could face life-long repeated surgeries due to recurrence of syndromes that decreases the quality of life. Thus, non-invasive treatments for Schwannoma are highly demanded. To discover novel therapeutics for non-invasive Schwannoma treatment, in this project, we leveraged the benefits of drug repurposing high-throughput screening (HTS) of FDA-approved drugs using 3D spheroids derived from Schwannoma patient samples. Both 2D primary cells and 3D primary spheroids models were developed from an IRB-approved tumor bank of schwannoma patient samples. The 3D spheroids were validated to recapitulate the features of patient tumors. We then conducted an ultra-HTS(uHTS) in 1536-well format of 2036 FDA-approved drugs on the growth and viability of Schwannoma patient-derived 3D spheroids. Seven FDA-approved drugs were identified from the pilot screen to inhibit the growth of Schwannoma patient-derived 3D spheroids. These drugs offer potential to serve as pharmacotherapeutics for Schwannoma non-invasive treatment. Our results have demonstrated the capability of a drug repurposing strategy for Schwannoma using uHTS and a patient-derived tumor bank. We further demonstrated that patient-derived drug sensitivity signatures could be encoded from the screening data to enable clustering of patients, which accounts for heterogeneity in Schwannoma and avoids "one-size-fits-all" solutions in future non-invasive Schwannoma treatment studies.
CTNI-26. EFFICACY AND SAFETY OF METFORMIN PLUS LOW-DOSE TEMOZOLOMIDE IN PATIENTS WITH RECURRENT OR REFRACTORY GLIOBLASTOMA: A RANDOMIZED, PROSPECTIVE, MULTICENTER, DOUBLE-BLIND, CONTROLLED, PHASE 2 TRIAL
Authors: Wan Soo Yoon, Jong Hee Chang, Jeong Hoon Kim, Yu Jung Kim, Tae Young Jung, Heon Yoo, Se-Hyuk Kim, Do-Hyun Nam, Tae Min Kim, Se Hoon Kim, Sung Hye Park, Youn Soo Lee, Hyeon Woo Kim, Yong-Kil Hong, Seung Ho Yang
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma(GBM) has a poor prognosis after standard treatment. Recently, metformin has been shown to have an antitumor effect on glioma cells. We performed the first randomized prospective phase II clinical trial to investigate the clinical efficacy and safety of meformin in patients with recurrent or refractory GBM treated with low-dose temozolomide (TMZ). Included patients were randomly assigned to a control group [placebo plus low-dose TMZ (50mg/m2, daily) or and experimental group [metformin (1,000mg, 1,500mg, and 2,000mg per day during the 1st, 2nd, and 3rd week until disease progression, respectively) plus low-dose TMZ]. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), disease control rate, overall response rate, health-related quality of life, and safety. Among the 92 patients screened, 81 were randomly assigned to the control group (43 patients) or the experimental group (38 patients). Although the control group showed a longer median PFS, the difference between the two groups was not statistically significant (2.66 versus 2.3 months, p = 0.679). The median OS was 17.22 months (95% CI:12.19-21.68 months) in the experimental group and 7.69 months (95% CI: 5.16-22.67 months) in the control group, showing no significant difference by the log-rank test (HR:0.78; 95% CI:0.39-1.58; p = 0.473). The overall response rate and disease control rate were 9.3% and 46.5% in the control group and 5.3% and 47.3% in the experimental group, respectively. Although the metformin plus TMZ regimen was well tolerated, it did not confer a clinical benefit in patients with recurrent or refractory GBM.